Caffino Lucia, Targa Giorgia, Mottarlini Francesca, Thielens Sarah, Rizzi Beatrice, Villers Agnes, Ris Laurence, Gainetdinov Raul R, Leo Damiana, Fumagalli Fabio
Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy.
Department of Neurosciences, University of Mons, Mons, Belgium.
Br J Pharmacol. 2025 Mar;182(6):1377-1393. doi: 10.1111/bph.17403. Epub 2024 Dec 9.
Slow-acting biogenic amines, such as dopamine, are known to modulate fast neurotransmitters e.g. glutamate. In the striatum, dopamine (DA) interacts with glutamate, influencing neural excitability and promoting synaptic plasticity. The exact mechanism of such interaction is not fully understood. This study investigates, in detail, how dopamine overactivity in dopamine transporter knockout (DAT) rats, alters the homeostasis of the striatal glutamate synapse from a molecular, behavioural and functional point of view.
The expression, localisation, retention and electrophysiological properties of N-methyl-D-aspartate (NMDA) receptors as well as dendritic spine density and morphology were investigated in the striatum of DAT rats, at baseline and after treatment with the non-competitive NMDA receptor antagonist memantine (30 mg kg).
Dopamine overactivity dramatically reorganises the striatal glutamate synapse, redistributing NMDA receptors in the synapse as typified by reduced synaptic availability and reduced expression of NMDA scaffolding proteins, as well as by increased GluN2B-containing NMDA receptors in the extra synapse. Such changes are accompanied by reduced spine density, suggesting dopamine-induced structural rearrangements. These results converge into a compromised plasticity, as shown by the impaired ability to promote long-term depression (LTD) in the striatum of DATrats. Notably, memantine counteracts hyperlocomotion, reverses spine alterations and abolishes the extrasynaptic movements of NMDA receptors in the striatum of DAT rats, thus restoring functional LTD.
A hyperdopaminergic condition seems to alter striatal homeostasis by increasing extrasynaptic NMDA receptors. These findings may be relevant to manipulate disorders characterised by elevated dopaminergic activity.
已知多巴胺等慢效生物胺可调节快速神经递质，如谷氨酸。在纹状体中，多巴胺（DA）与谷氨酸相互作用，影响神经兴奋性并促进突触可塑性。这种相互作用的确切机制尚未完全了解。本研究从分子、行为和功能角度详细探究多巴胺转运体敲除（DAT）大鼠中多巴胺活性过高如何改变纹状体谷氨酸突触的稳态。
在DAT大鼠纹状体的基线期以及用非竞争性NMDA受体拮抗剂美金刚（30mg/kg）治疗后，研究N-甲基-D-天冬氨酸（NMDA）受体的表达、定位、保留和电生理特性以及树突棘密度和形态。
多巴胺活性过高显著重组纹状体谷氨酸突触，使突触中的NMDA受体重新分布，表现为突触可用性降低、NMDA支架蛋白表达减少，以及突触外含GluN2B的NMDA受体增加。这些变化伴随着树突棘密度降低，提示多巴胺诱导的结构重排。这些结果共同导致可塑性受损，如DAT大鼠纹状体中促进长时程抑制（LTD）的能力受损所示。值得注意的是，美金刚可抵消运动亢进，逆转树突棘改变，并消除DAT大鼠纹状体中NMDA受体的突触外移动，从而恢复功能性LTD。
多巴胺能亢进状态似乎通过增加突触外NMDA受体来改变纹状体稳态。这些发现可能与治疗以多巴胺能活性升高为特征的疾病有关。
